Cotton fabrics are widely used in everyday life; however, increasing their versatility through green modifications remains a challenge. The current mainstream approach merely physically attaches the additives onto the fibers, resulting in low binding affinity. In this study, novel cotton fabrics (Cotton-Si-EU) with long-lasting antibacterial, anti-mite, and mosquito-repellent properties were facilely fabricated in a green procedure. In contrast to conventional coating and physical addition methods, the eugenol graft modification ensured the safety, environmental friendliness and long-lasting functionality of the Cotton-Si-EU. In addition, Cotton-Si-EU fabrics retained the softness, comfort, breathability, and moisture absorption originating from the cotton fabric. Cotton-Si-EU also showed over 99.99% antibacterial, 73% anti-mite, and 75% mosquito repellent rates, simultaneously destroying microorganisms and insects through oxidative stress, inhibiting enzyme activity, affecting cell structure, and other mechanisms. More importantly, after 50 washing cycles, the fabrics still exhibited durable antibacterial properties higher than the AAA requirements, indicating high functional longevity. In addition, good cytocompatibility, hemocompatibility, and negligible skin irritation demonstrated excellent biological safety. Therefore, this study is of great significance in providing a reference for modifying cotton fabrics using an infinite number of natural products after screening, which will broaden the application scope and improve the safety level of functional cotton fabrics.